1. Field of the Invention
Agents that alter the transport activity of small, neutrally charged solutes by solute transporters and agents that alter transport of water by aquaporins are needed as therapeutic agents for increasing solute clearance in states of fluid overload and for treating diseases, disorders, and conditions such as hypertension. Methods for identifying and using agents that inhibit solute transporters and aquaporins are described herein.
2. Description of the Related Art
Diuretics are administered widely in humans to increase renal salt and water clearance in a variety of conditions that are associated with total body fluid overload, such as congestive heart failure and cirrhosis, as well in normovolemic states such as hypertension and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Most diuretics are inhibitors of salt absorption by kidney tubules, such as a furosemide block of Na+/K+/2Cl− co-transport in the thick ascending limb of Henle and a thiazide block of Na+/Cl− co-transport in the distal tubule. Recently, a new type of diuretic, called an “aquaretic,” has been developed to increase renal water clearance in hyponatremia associated with fluid overload or SIADH (see, e.g., Goldsmith, Am. J. Cardiol. 95:14 B-23B (2005); Miller, J. Am. Geriatr. Soc. 54:345-53 (2006)). Vasopressin-2 receptor (V2R) antagonist aquaretics have been approved for clinical use in some countries, though not yet in the United States, and aquaporin inhibitor aquaretics are under development.
Functional studies in knock-out mice indicate a critical role for solute transporters, such as urea transporters (UTs), in the urinary concentrating mechanism and in renal urea clearance. However, potent and specific urea transport blockers have not been available. Accordingly, a third type of diuretic is needed: one that targets renal urea clearance mechanisms. Because urea is of at least equal importance to NaCl in the renal countercurrent mechanism for urinary concentration (see, e.g., Bankir et al., supra; Masilamani et al., In The Kidney (6th Edition), Brenner, ed. Philadelphia, Pa.; WB Saunders Company; pages 595-35; (2000)), such diuretics are needed for increasing solute clearance in states of fluid overload, for treating hypertension, and may also be useful in prolonging dialysis-free survival in chronic renal insufficiency. Therapeutic molecules are needed that are capable of effectively increasing renal water and solute clearance in subjects who are exhibiting a water-retaining state.
Thus, a need exists for methods that permit rapid screening and characterization of large numbers of agents to identify agents that alter the transport activity of solute transporters, such as agents that alter the transport activity of urea transporters. Methods are also needed in the art for rapid screening and identification of agents that alter the transport activity of aquaporins.